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1.  In Vivo Lamina Cribrosa Micro-Architecture in Healthy and Glaucomatous Eyes as Assessed by Optical Coherence Tomography 
The lamina cribrosa (LC) is a prime location of glaucomatous damage. The purpose of this study was to compare LC 3-dimensional micro-architecture between healthy and glaucomatous eyes in vivo by using optical coherence tomography (OCT).
Sixty-eight eyes (19 healthy and 49 glaucomatous) from 47 subjects were scanned in a 3.5 × 3.5 × 3.64-mm volume (400 × 400 × 896 pixels) at the optic nerve head by using swept-source OCT. The LC micro-architecture parameters were measured on the visible LC by an automated segmentation algorithm. The LC parameters were compared to diagnosis and visual field mean deviation (VF MD) by using a linear mixed effects model accounting for age.
The average VF MD for the healthy and glaucomatous eyes was −0.50 ± 0.80 dB and −7.84 ± 8.75 dB, respectively. Beam thickness to pore diameter ratio (P = 0.04) and pore diameter standard deviation (P < 0.01) were increased in glaucomatous eyes. With worse MD, beam thickness to pore diameter ratio (P < 0.01), pore diameter standard deviation (P = 0.05), and beam thickness (P < 0.01) showed a statistically significant increase while pore diameter (P = 0.02) showed a significant decrease. There were no significant interactions between any of the parameters and age (all P > 0.05).
Glaucomatous micro-architecture changes in the LC, detected by OCT analysis, reflect beams remodeling and axonal loss leading to reduction in pore size and increased pore size variability.
Using swept-source OCT we demonstrated in vivo significant differences in the lamina cribrosa micro-architecture between healthy and glaucomatous eyes. These changes reflect beams remodeling and axonal loss leading to reduction in pore size and increased pore size variability.
PMCID: PMC3869422  PMID: 24302585
lamina cribrosa; optical coherence tomography; glaucoma
2.  Reproducibility of In-Vivo OCT Measured Three-Dimensional Human Lamina Cribrosa Microarchitecture 
PLoS ONE  2014;9(4):e95526.
To determine the reproducibility of automated segmentation of the three-dimensional (3D) lamina cribrosa (LC) microarchitecture scanned in-vivo using optical coherence tomography (OCT).
Thirty-nine eyes (8 healthy, 19 glaucoma suspects and 12 glaucoma) from 49 subjects were scanned twice using swept-source (SS−) OCT in a 3.5×3.5×3.64 mm (400×400×896 pixels) volume centered on the optic nerve head, with the focus readjusted after each scan. The LC was automatically segmented and analyzed for microarchitectural parameters, including pore diameter, pore diameter standard deviation (SD), pore aspect ratio, pore area, beam thickness, beam thickness SD, and beam thickness to pore diameter ratio. Reproducibility of the parameters was assessed by computing the imprecision of the parameters between the scans.
The automated segmentation demonstrated excellent reproducibility. All LC microarchitecture parameters had an imprecision of less or equal to 4.2%. There was little variability in imprecision with respect to diagnostic category, although the method tends to show higher imprecision amongst healthy subjects.
The proposed automated segmentation of the LC demonstrated high reproducibility for 3D LC parameters. This segmentation analysis tool will be useful for in-vivo studies of the LC.
PMCID: PMC3991692  PMID: 24747957
3.  Repeatability of in vivo 3D lamina cribrosa microarchitecture using adaptive optics spectral domain optical coherence tomography 
Biomedical Optics Express  2014;5(4):1114-1123.
We demonstrate the repeatability of lamina cribrosa (LC) microarchitecture for in vivo 3D optical coherence tomography (OCT) scans of healthy, glaucoma suspects, and glaucomatous eyes. Eyes underwent two scans using a prototype adaptive optics spectral domain OCT (AO-SDOCT) device from which LC microarchitecture was semi-automatically segmented. LC segmentations were used to quantify pore and beam structure through several global microarchitecture parameters. Repeatability of LC microarchitecture was assessed qualitatively and quantitatively by calculating parameter imprecision. For all but one parameters (pore volume) measurement imprecision was <4.7% of the mean value, indicating good measurement reproducibility. Imprecision ranged between 27.3% and 54.5% of the population standard deviation for each parameter, while there was not a significant effect on imprecision due to disease status, indicating utility in testing for LC structural trends.
PMCID: PMC3986004  PMID: 24761293
(100.2000) Digital image processing; (170.4470) Ophthalmology; (110.4500) Optical coherence tomography; (170.1610) Clinical applications; (330.4460) Ophthalmic optics and devices
4.  Gold Nanorods as a Contrast Agent for Doppler Optical Coherence Tomography 
PLoS ONE  2014;9(3):e90690.
To investigate gold nanorods (GNRs) as a contrast agent to enhance Doppler optical coherence tomography (OCT) imaging of the intrascleral aqueous humor outflow.
A serial dilution of GNRs was scanned with a spectral-domain OCT device (Bioptigen, Durham, NC) to visualize Doppler signal. Doppler measurements using GNRs were validated using a controlled flow system. To demonstrate an application of GNR enhanced Doppler, porcine eyes were perfused at constant pressure with mock aqueous alone or 1.0×1012 GNR/mL mixed with mock aqueous. Twelve Doppler and volumetric SD-OCT scans were obtained from the limbus in a radial fashion incremented by 30°, forming a circular scan pattern. Volumetric flow was computed by integrating flow inside non-connected vessels throughout all 12 scans around the limbus.
At the GNR concentration of 0.7×1012 GNRs/mL, Doppler signal was present through the entire depth of the testing tube without substantial attenuation. A well-defined laminar flow profile was observed for Doppler images of GNRs flowing through the glass capillary tube. The Doppler OCT measured flow profile was not statistically different from the expected flow profile based upon an autoregressive moving average model, with an error of −0.025 to 0.037 mm/s (p = 0.6435). Cross-sectional slices demonstrated the ability to view anterior chamber outflow ex-vivo using GNR-enhanced Doppler OCT. Doppler volumetric flow measurements were comparable to flow recorded by the perfusion system.
GNRs created a measureable Doppler signal within otherwise silent flow fields in OCT Doppler scans. Practical application of this technique was confirmed in a constant pressure ex-vivo aqueous humor outflow model in porcine eyes.
PMCID: PMC3940929  PMID: 24595044
5.  CDKN2B-AS1 Genotype – Glaucoma Feature Correlations in Primary Open-Angle Glaucoma Patients from the United States 
American journal of ophthalmology  2012;155(2):342-353.e5.
To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients.
Retrospective observational case series.
We studied associations between ten CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results.
For nine of the ten protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (e.g., the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: −0.08, −0.03; p=6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P=5.45E-06). For the one adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P=4.74E-04) despite having lower IOP (−0.57 mm Hg per A allele at DNA collection; 95% CI: −0.84, −0.29; P=6.55E-05).
Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.
PMCID: PMC3544983  PMID: 23111177
6.  Combining Information from Three Anatomic Regions in the Diagnosis of Glaucoma with Time-Domain Optical Coherence Tomography 
Journal of glaucoma  2012;10.1097/IJG.0b013e318264b941.
To improve the diagnosis of glaucoma by combining time-domain optical coherence tomography (TD-OCT) measurements of the optic disc, circumpapillary retinal nerve fiber layer (RNFL), and macular retinal thickness.
Patients and Methods
Ninety-six age-matched normal and 96 perimetric glaucoma participants were included in this observational, cross-sectional study. Or-logic, support vector machine (SVM), relevance vector machine (RVM), and linear discrimination function (LDF) were used to analyze the performances of combined TD-OCT diagnostic variables.
The area under the receiver operating curve (AROC) was used to evaluate the diagnostic accuracy and to compare the diagnostic performance of single and combined anatomic variables. The best RNFL thickness variables were the inferior (AROC=0.900), overall (AROC=0.892), and superior quadrants (AROC=0.850). The best optic disc variables were horizontal integrated rim width (AROC=0.909), vertical integrated rim area (AROC=0.908), and cup/disc vertical ratio (AROC=0.890). All macular retinal thickness variables had AROCs of 0.829 or less. Combining the top 3 RNFL and optic disc variables in optimizing glaucoma diagnosis, SVM had the highest AROC, 0.954, followed by or-logic (AROC=0.946), LDF (AROC=0.946), and RVM (AROC=0.943). All combination diagnostic variables had significantly larger AROCs than any single diagnostic variable. There are no significant differences among the combination diagnostic indices.
With TD-OCT, RNFL and optic disc variables had better diagnostic accuracy than macular retinal variables. Combining top RNFL and optic disc variables significantly improved diagnostic performance. Clinically, or-logic classification was the most practical analytical tool with sufficient accuracy to diagnose early glaucoma.
PMCID: PMC3535579  PMID: 22828002
optical coherence tomography; glaucoma; imaging; image processing
7.  Retinal Nerve Fiber Layer Atrophy Is Associated with Visual Field Loss over Time in Glaucoma Suspect and Glaucomatous Eyes 
American journal of ophthalmology  2012;155(1):73-82.e1.
To prospectively compare detection of progressive retinal nerve fiber layer thickness (RNFL) atrophy identified using time-domain optical coherence tomography (OCT) with visual field progression using standard automated perimetry (SAP) in glaucoma suspect and preperimetric glaucoma and perimetric glaucoma patients.
Prospective longitudinal clinical trial
Eligible eyes with ≥2 years of follow-up underwent time-domain OCT and SAP every 6 months. The occurrence of visual field progression was defined as the first follow-up visit reaching a significant (p<0.05) negative visual field index (VFI) slope over time. RNFL progression/improvement was defined as a significant negative/positive slope over time. Specificity was defined as the number of eyes with neither progression nor improvement, divided by the number of eyes without progression. Cox proportional hazard ratios (HR) were calculated using univariate and multivariate models with RNFL loss as a time-dependent covariate.
310 glaucoma suspect and preperimetric glaucoma, and 177 perimetric glaucoma eyes were included. Eighty-nine eyes showed visual field progression and 101 eyes showed RNFL progression. The average time to detect visual field progression in those 89 eyes was 35±13 months; and to detect RNFL progression in those 101 eyes was 36±13 months. In multivariate Cox models, average and superior RNFL losses were associated with subsequent VFI loss in the entire cohort (every 10μm loss, HR=1.38,p=0.03; HR=1.20, p=0.01 respectively). Among the entire cohort of 487 eyes, 42 had significant VFI improvement and 55 had significant RNFL improvement (specificity 91.4% and 88.7%, respectively).
Structural progression is associated with functional progression in glaucoma suspect and glaucomatous eyes. Average and superior RNFL thickness may predict subsequent SAP loss.
PMCID: PMC3525739  PMID: 23036570
retinal nerve fiber layer; visual field; glaucoma progression; hazard ratio
8.  Individual A-Scan Signal Normalization Between Two Spectral Domain Optical Coherence Tomography Devices 
We developed a method to normalize optical coherence tomography (OCT) signal profiles from two spectral-domain (SD) OCT devices so that the comparability between devices increases.
We scanned 21 eyes from 14 healthy and 7 glaucoma subjects with two SD-OCT devices on the same day, with equivalent cube scan patterns centered on the fovea (Cirrus HD-OCT and RTVue). Foveola positions were selected manually and used as the center for registration of the corresponding images. A-scan signals were sampled 1.8 mm from the foveola in the temporal, superior, nasal, and inferior quadrants. After oversampling and rescaling RTVue data along the Z-axis to match the corresponding Cirrus data format, speckle noise reduction and amplitude normalization were applied. For comparison between normalized A-scan profiles, mean absolute difference in amplitude in percentage was measured at each sampling point. As a reference, the mean absolute difference between two Cirrus scans on the same eye also was measured.
The mean residual of the A-scan profile amplitude was reduced significantly after signal normalization (12.7% vs. 6.2%, P < 0.0001, paired t-test). All four quadrants also showed statistically significant reduction (all P < 0.0001). Mean absolute difference after normalization was smaller than the one between two Cirrus scans. No performance difference was detected between health and glaucomatous eyes.
The reported signal normalization method successfully reduced the A-scan profile differences between two SD-OCT devices. This signal normalization processing may improve the direct comparability of OCT image analysis and measurement on various devices.
A novel signal normalization method for SD-OCT images was developed and tested to improve the direct comparability of image analysis and clinical measurements between devices. The A-scan profile differences between 2 SD-OCT devices were reduced significantly after normalization.
PMCID: PMC3658265  PMID: 23611992
optical coherence tomography; image analysis; comparability
9.  Automated lamina cribrosa microstructural segmentation in optical coherence tomography scans of healthy and glaucomatous eyes 
Biomedical Optics Express  2013;4(11):2596-2608.
We demonstrate an automated segmentation method for in-vivo 3D optical coherence tomography (OCT) imaging of the lamina cribrosa (LC). Manual segmentations of coronal slices of the LC were used as a gold standard in parameter selection and evaluation of the automated technique. The method was validated using two prototype OCT devices; each had a subject cohort including both healthy and glaucomatous eyes. Automated segmentation of in-vivo 3D LC OCT microstructure performed comparably to manual segmentation and is useful for investigative research and in clinical quantification of the LC.
PMCID: PMC3829553  PMID: 24298418
(100.2000) Digital image processing; (170.4470) Ophthalmology; (110.4500) Optical coherence tomography; (170.1610) Clinical applications; (330.4460) Ophthalmic optics and devices
10.  Optic Nerve Head and Retinal Nerve Fiber Layer Analysis 
Ophthalmology  2007;114(10):1937-1949.
To evaluate the current published literature on the use of optic nerve head (ONH) and retinal nerve fiber layer (RNFL) measurement devices in diagnosing open-angle glaucoma and detecting progression.
A search of peer-reviewed literature was conducted on February 15, 2006 in PubMed and the Cochrane Library for the period January 2003 to February 2006. The search was limited to studies of adults in English-language journals and yielded 442 citations. The panel reviewed the abstracts of these articles and selected 159 articles of possible clinical relevance for review. Of these 159 full-text articles, 82 were determined to be relevant for the first author and methodologist to review and rate according to the quality of evidence.
There were no studies classified as having the highest level of evidence (level I). The ONH and RNFL imaging instruments reviewed in this assessment were determined to be highly effective in distinguishing eyes with glaucomatous visual field (VF) loss from normal eyes without VF loss, based on level II evidence. In addition, some studies demonstrated that parameters from ONH or RNFL imaging predicted the development of VF defects among glaucoma suspects. Studies on detecting glaucoma progression showed that although there was often agreement on progression between the structural and functional (VF) tests, a significant proportion of glaucoma patients progressed by either the structural or the functional test alone.
The ONH and RNFL imaging devices provide quantitative information for the clinician. Based on studies that have compared the various available technologies directly, there is no single imaging device that outperforms the others in distinguishing patients with glaucoma from controls. Ongoing advances in imaging and related software, as well as the impracticalities associated with obtaining and assessing optic nerve stereophotographs, have made imaging increasingly important in many practice settings. The information obtained from imaging devices is useful in clinical practice when analyzed in conjunction with other relevant parameters that define glaucoma diagnosis and progression.
PMCID: PMC3780976  PMID: 17908595
11.  Advanced scanning methods with tracking optical coherence tomography 
Optics express  2005;13(20):7937-7947.
An upgraded optical coherence tomography system with integrated retinal tracker (TOCT) was developed. The upgraded system uses improved components to extend the tracking bandwidth, fully integrates the tracking hardware into the optical head of the clinical OCT system, and operates from a single software platform. The system was able to achieve transverse scan registration with sub-pixel accuracy (~10 μm). We demonstrate several advanced scan sequences with the TOCT, including composite scans averaged (co-added) from multiple B-scans taken consecutively and several hours apart, en face images collected by summing the A-scans of circular, line, and raster scans, and three-dimensional (3D) retinal maps of the fovea and optic disc. The new system achieves highly accurate OCT scan registration yielding composite images with significantly improved spatial resolution, increased signal-to-noise ratio, and reduced speckle while maintaining well-defined boundaries and sharp fine structure compared to single scans. Precise re-registration of multiple scans over separate imaging sessions demonstrates TOCT utility for longitudinal studies. En face images and 3D data cubes generated from these data reveal high fidelity image registration with tracking, despite scan durations of more than one minute.
PMCID: PMC3763241  PMID: 19498823
12.  Evaluating Objective and Subjective Quantitative Parameters at the Initial Visit to Predict Future Glaucomatous Visual Field Progression 
To evaluate the ability of structural assessment to predict glaucomatous visual field progression.
A total of 119 healthy eyes with suspected glaucoma and glaucomatous eyes with 5 or more optic nerve stereophotographs, optical coherence tomography (OCT), and confocal scanning laser ophthalmoscopy (CSLO) all acquired within 6 months of each other were enrolled. Odds ratios to predict progression were determined by generalized estimating equation models.
Median follow-up was 4.0 years (range: 1.5 to 5.7 years). Fifteen eyes progressed by glaucoma progression analysis, 20 by visual field index, and 10 by both. Baseline parameters from stereophotographs (vertical cup-to-disc ratio and Disc Damage Likelihood Scale), OCT (global, superior quadrant, and inferior quadrant retinal nerve fiber layer thickness), and CSLO (cup shape measure and mean cup depth) were significant predictors of progression. Comparing the single best parameter from all models, only the OCT superior quadrant RNFL predicted progression.
Baseline stereophotographs, OCT, and CSLO measurements may be clinically useful to predict glaucomatous visual field progression.
PMCID: PMC3444548  PMID: 22658308
13.  Visualization of the Conventional Outflow Pathway in the Living Human Eye 
Ophthalmology  2012;119(8):1563-1568.
The purpose of this study was to visualize the aqueous outflow system in three dimensions (3D) in living human eyes, and to investigate the use of commercially available Spectral-domain optical coherence tomographic (SD-OCT) systems for this purpose.
This was a prospective observational study.
Participants and/or Controls
One randomly determined eye in each of six normal healthy subjects was included.
3D SD-OCT imaging of the aqueous humor outflow structures was performed with two devices: Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin CA) and Bioptigen SDOIS (Bioptigen, Inc., Research Triangle, NC).
Main Outcome Measures
3D virtual castings of Schlemm’s canal (SC) and more distal outflow structures created from scan data from each device.
Virtual casting of SC provided visualization of more aqueous vessels branching from SC than could be located by interrogating the 2D image stack. Similarly, virtual casting of distal structures allowed visualization of large and small aqueous outflow channel networks that could not be appreciated with the conventional 2D visualization.
The outflow pathways from SC to the superficial vasculature can be identified and tracked in living human eyes using commercially available SD-OCT.
PMCID: PMC3411861  PMID: 22683063
14.  Glaucoma Discrimination of Segmented Cirrus Spectral Domain Optical Coherence Tomography (SD-OCT) Macular Scans 
The British journal of ophthalmology  2012;96(11):1420-1425.
To evaluate the glaucoma discriminating ability of macular retinal layers as measured by spectral-domain optical coherence tomography (SD-OCT).
Healthy, glaucoma suspect and glaucomatous subjects had a comprehensive ocular examination, visual field testing and SD-OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) in the macular and optic nerve head regions. OCT macular scans were segmented into macular nerve fiber layer (mNFL), ganglion cell layer with inner plexiform layer (GCIP), ganglion cell complex (GCC) (composed of mNFL and GCIP), outer retinal complex (ORC) and total retina (TR). Glaucoma discriminating ability was assessed using the area under the receiver operator characteristic curve (AUC) for all macular parameters and mean circumpapillary (cp) RNFL. Glaucoma suspects and glaucoma subjects were grouped together for the calculation of AUCs.
Analysis was performed on 51 healthy, 49 glaucoma suspect and 63 glaucomatous eyes. The median visual field MD was −2.21dB (interquartile range (IQR): −6.92 to −0.35) for the glaucoma group, −0.32dB (IQR: −1.22 to 0.73) for the suspect group and −0.18dB (IQR: −0.92 to 0.71) for the healthy group. Highest age adjusted AUCs for discriminating between healthy and glaucomatous eyes were found for average GCC and GCIP (AUC=0.901 and 0.900, respectively), and their sectoral measurements: infero-temporal (0.922 and 0.913), inferior (0.904 and 0.912) and supero-temporal (0.910 and 0.897). These values were similar to the discriminating ability of the mean cpRNFL (AUC=0.913). Comparison of these AUCs did not yield any statistically significant difference (all p>0.05). Similar discrimination performance but with slight reduction in AUCs was achieved for comparison between healthy and the combination of glaucoma and glaucoma suspect eyes.
SD-OCT GCIP and GCC measurements showed similar glaucoma diagnostic ability and was comparable with that of cpRNFL.
PMCID: PMC3721629  PMID: 22914498
15.  Detection of Glaucoma Progression by Population and Individual Derived Variability Criteria 
Ocular imaging devices provide quantitative structural information that might improve glaucoma progression detection. This study examined scanning laser polarimetry (SLP) population-derived versus individual-derived cut-off criteria for detecting progression.
Forty-eight healthy, glaucoma suspect and glaucoma subjects, providing 76 eyes were used. All subjects had reliable visual field (VF) and SLP scans acquired at the same visits from ≥ 4 visits. VF progression was defined by guided progression analysis (GPA) and by the VF index (VFI). SLP measurements were analyzed by fast mode (FM) GPA, compared to the population rate of progression, and extended mode (EM) GPA, compared to the individual variability. The agreement between progression detection methods was measured.
Poor agreement was observed between progression defined by VF and FM and EM. The difference in TSNIT average rate of change between VF defined progressors and non-progressors for both FM (p=0.010) and EM (p=0.015) was statistically significant.
There is poor agreement between VF and SLP progression regardless of the use of population derived or individual variability criteria. The best SLP progression detection method could not be ascertained, therefore, acquiring three SLP scans per visit is recommended.
PMCID: PMC3721630  PMID: 23203702
Scanning laser polarimetry; glaucoma progression
16.  Automated Foveola Localization in Retinal 3D-OCT Images Using Structural Support Vector Machine Prediction 
We develop an automated method to determine the foveola location in macular 3D-OCT images in either healthy or pathological conditions. Structural Support Vector Machine (S-SVM) is trained to directly predict the location of the foveola, such that the score at the ground truth position is higher than that at any other position by a margin scaling with the associated localization loss. This S-SVM formulation directly minimizes the empirical risk of localization error, and makes efficient use of all available training data. It deals with the localization problem in a more principled way compared to the conventional binary classifier learning that uses zero-one loss and random sampling of negative examples. A total of 170 scans were collected for the experiment. Our method localized 95.1% of testing scans within the anatomical area of the foveola. Our experimental results show that the proposed method can effectively identify the location of the foveola, facilitating diagnosis around this important landmark.
PMCID: PMC3717593  PMID: 23285565
17.  Macula assessment using optical coherence tomography for glaucoma diagnosis 
The British journal of ophthalmology  2012;96(12):1452-1455.
Optical coherence tomography (OCT) is an interferometry-based imaging modality that generates high-resolution cross-sectional images of the retina. Circumpapillary retinal nerve fiber layer (cpRNFL) and optic nerve head assessments are the mainstay of glaucomatous structural measurements in OCT. However, because these measurements are not always available or precise, it would be useful to have another reliable indicator. The macula has been suggested as an alternative scanning location for glaucoma diagnosis. Using time-domain (TD-) OCT, macular measurements have shown to provide good glaucoma diagnostic capabilities. With the adoption of spectral-domain OCT, which allows a higher image resolution than TD-OCT, segmentation of inner macular layers becomes possible. These layers are specifically prone to glaucomatous damage and thickness measurements show a comparable performance to that of glaucomatous cpRNFL measurements. The role of macular measurements for detection of glaucoma progression is still under investigation. More sophisticated measurement and analysis tools that can amplify the advantages of macular measurements are expected. For example, improvement of image quality would allow better visualization, development of various scanning modes would optimize macular measurements, and further refining of the analytical algorithm would provide more accurate segmentation. With these achievements, macular measurement can be an important surrogate for glaucomatous structural assessment.
PMCID: PMC3718015  PMID: 23018425
18.  Inflammatory Response to Intravitreal Injection of Gold Nanorods 
The British journal of ophthalmology  2012;96(12):1522-1529.
To evaluate the utility of gold nanorods (AuNRs) as a contrast agent for ocular optical coherence tomography (OCT).
Mice were intravitreally injected with sterile AuNRs coated with either poly(strenesulfate) (PSS-AuNRs) or anti-CD90.2 antibodies (Ab-AuNRs), and imaged using OCT. After 24 hours, eyes were processed for transmission electron microscopy or rendered into single cell suspensions for flow cytometric analysis to determine absolute numbers of CD45+ leukocytes and subsets (T cells, myeloid cells, macrophages, neutrophils). Generalized estimation equations were used to compare cell counts between groups.
PSS-AuNRs and Ab-AuNRs were visualized in the vitreous 30min and 24h post- injection with OCT. At 24h, a statistically significant increase in leukocytes, comprised primarily of neutrophils, was observed in eyes that received either AuNR in comparison to eyes that received saline. The accumulation of leukocytes was equal in eyes given PSS-AuNR or Ab- AuNR. Endotoxin-resistant C3H/HeJ mice also showed ocular inflammation after injection with AuNRs, indicating that the inflammatory response was not due to lipopolysaccharide contamination of AuNRs.
Although AuNRs can be visualized in the eye using OCT they can induce ocular inflammation, which limits their use as a contrast agent.
PMCID: PMC3718482  PMID: 23087415
gold nanoparticles; optical coherence tomography; contrast enhancement; immune response
19.  Normative optical coherence tomography measurements in children 
PMCID: PMC3417148  PMID: 22426801
20.  Alignment of 3-D Optical Coherence Tomography Scans to Correct Eye Movement Using a Particle Filtering 
IEEE transactions on medical imaging  2012;31(7):1337-1345.
Eye movement artifacts occurring during 3-D optical coherence tomography (OCT) scanning is a well-recognized problem that may adversely affect image analysis and interpretation. A particle filtering algorithm is presented in this paper to correct motion in a 3-D dataset by considering eye movement as a target tracking problem in a dynamic system. The proposed particle filtering algorithm is an independent 3-D alignment approach, which does not rely on any reference image. 3-D OCT data is considered as a dynamic system, while the location of each A-scan is represented by the state space. A particle set is used to approximate the probability density of the state in the dynamic system. The state of the system is updated frame by frame to detect A-scan movement. The proposed method was applied on both simulated data for objective evaluation and experimental data for subjective evaluation. The sensitivity and specificity of the x-movement detection were 98.85% and 99.43%, respectively, in the simulated data. For the experimental data (74 3-D OCT images), all the images were improved after z-alignment, while 81.1% images were improved after x-alignment. The proposed algorithm is an efficient way to align 3-D OCT volume data and correct the eye movement without using references.
PMCID: PMC3417150  PMID: 22231171
Eye movement correction; particle filtering; retinal image processing; three-dimensional optical coherence tomography (3-D OCT)
21.  High Dynamic Range Imaging Concept-Based Signal Enhancement Method Reduced the Optical Coherence Tomography Measurement Variability 
To develop and test a novel signal enhancement method for optical coherence tomography (OCT) images based on the high dynamic range (HDR) imaging concept.
Three virtual channels, which represent low, medium, and high signal components, were produced for each OCT signal dataset. The dynamic range of each signal component was normalized to the full gray scale range. Finally, the three components were recombined into one image using various weights. Fourteen eyes of 14 healthy volunteers were scanned multiple times using time-domain (TD)-OCT before and while preventing blinking in order to produce a wide variety of signal strength (SS) images on the same eye scanned on the same day. For each eye, a pair of scans with the highest and lowest SS with successful retinal nerve fiber layer (RNFL) segmentation was selected to test the signal enhancement effect. In addition, spectral-domain (SD)-OCT images with poor signal qualities were also processed.
Mean SS of good and poor quality scans were 9.0 ± 1.1 and 4.4 ± 0.9, respectively. TD-OCT RNFL thickness showed significant differences between good and poor quality scans on the same eye (mean difference 11.9 ± 6.0 μm, P < 0.0001, paired t-test), while there was no significant difference after signal enhancement (1.7 ± 6.2 μm, P = 0.33). However, HDR had weaker RNFL compensation effect on images with SS less than or equal to 4, while it maintained good compensation effect on images with SS greater than 4. Successful signal enhancement was also confirmed subjectively on SD-OCT images.
The HDR imaging successfully restored OCT signal and image quality and reduced RNFL thickness differences due to variable signal level to the level within the expected measurement variability. This technique can be applied to both TD- and SD-OCT images.
A novel signal enhancement method for optical coherence tomography images was developed based on the high dynamic range imaging concept, which minimized the retinal nerve fiber layer thickness differences due to various signal levels.
PMCID: PMC3562131  PMID: 23299477
22.  Ganglion Cell Loss in Relation to Visual Disability in Multiple Sclerosis 
Ophthalmology  2012;119(6):1250-1257.
We used high-resolution spectral-domain optical coherence tomography (SD-OCT) with retinal segmentation to determine how ganglion cell loss relates to history of acute optic neuritis (ON), retinal nerve fiber layer (RNFL) thinning, visual function, and vision-related quality of life (QOL) in multiple sclerosis (MS).
Cross-sectional study.
A convenience sample of patients with MS (n = 122; 239 eyes) and disease-free controls (n = 31; 61 eyes). Among MS eyes, 87 had a history of ON before enrollment.
The SD-OCT images were captured using Macular Cube (200×200 or 512×128) and ONH Cube 200×200 protocols. Retinal layer segmentation was performed using algorithms established for glaucoma studies. Thicknesses of the ganglion cell layer/inner plexiform layer (GCL+IPL), RNFL, outer plexiform/inner nuclear layers (OPL+INL), and outer nuclear/photoreceptor layers (ONL+PRL) were measured and compared in MS versus control eyes and MS ON versus non-ON eyes. The relation between changes in macular thickness and visual disability was also examined.
Main Outcome Measures
The OCT measurements of GCL+IPL and RNFL thickness; high contrast visual acuity (VA); low-contrast letter acuity (LCLA) at 2.5% and 1.25% contrast; on the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement composite score.
Macular RNFL and GCL+IPL were significantly decreased in MS versus control eyes (P<0.001 and P = 0.001) and in MS ON versus non-ON eyes (P<0.001 for both measures). Peripapillary RNFL, macular RNFL, GCL+IPL, and the combination of macular RNFL+GCL+IPL were significantly correlated with VA (P≤0.001), 2.5% LCLA (P<0.001), and 1.25% LCLA (P≤0.001). Among OCT measurements, reductions in GCL+IPL (P<0.001), macular RNFL (P = 0.006), and the combination (macular RNFL+GCL+IPL; P<0.001) were most strongly associated with lower (worse) NEI-VFQ-25 and 10-Item Supplement QOL scores; GCL+IPL thinning was significant even accounting for macular RNFL thickness (P = 0.03 for GCL+IPL, P = 0.39 for macular RNFL).
We demonstrated that GCL+IPL thinning is most significantly correlated with both visual function and vision-specific QOL in MS, and may serve as a useful structural marker of disease. Our findings parallel those of magnetic resonance imaging studies that show gray matter disease is a marker of neurologic disability in MS.
PMCID: PMC3631566  PMID: 22365058
23.  Optical Coherence Tomography: Future Trends for Imaging in Glaucoma 
Optometry and Vision Science  2012;89(5):E554-E562.
Optical coherence tomography (OCT) captures a major role in clinical assessment in eye care. Innovative hardware and software improvements in the technology would further enhance its usefulness. In this review we present several promising initiatives currently in development or early phase of assessment that we expect to have a future impact on OCT.
PMCID: PMC3348373  PMID: 22488265
optical coherence tomography; OCT; image processing
24.  Clinical Application of Ocular Imaging 
Optometry and Vision Science  2012;89(5):E543-E553.
The broadening frontier of technology used in ocular imaging is continuously affecting the landscape of clinical eye care. With each wave of enhanced imaging modalities, the field faces the difficulties of optimally incorporating these devices into the clinic. Ocular imaging devices have been widely incorporated into clinical management after their diagnostic capabilities have been documented in a wide range of ocular disease. In this review we are presenting the main commercially available devices for imaging of the posterior segment of the eye.
PMCID: PMC3348430  PMID: 22488266
ocular imaging devices; optical coherence tomography; scanning laser ophthalmoscopy; scanning laser polarimetry
25.  Variation in optical coherence tomography signal quality as an indicator of retinal nerve fibre layer segmentation error 
Commercial optical coherence tomography (OCT) systems use global signal quality indices to quantify scan quality. Signal quality can vary throughout a scan, contributing to local retinal nerve fibre layer segmentation errors (SegE). The purpose of this study was to develop an automated method, using local scan quality, to predict SegE.
Good-quality (global signal strength (SS)≥6; manufacturer specification) peripapillary circular OCT scans (fast retinal nerve fibre layer scan protocol; Stratus OCT; Carl Zeiss Meditec, Dublin, California, USA) were obtained from 6 healthy, 19 glaucoma-suspect and 43 glaucoma subjects. Scans were grouped based on SegE. Quality index (QI) values were computed for each A-scan using software of our own design. Logistic mixed-effects regression modelling was applied to evaluate SS, global mean and SD of QI, and the probability of SegE.
The difference between local mean QI in SegE regions and No-SegE regions was −5.06 (95% CI −6.38 to 3.734) (p<0.001). Using global mean QI, QI SD and their interaction term resulted in the model of best fit (Akaike information criterion=191.8) for predicting SegE. Global mean QI≥20 or SS≥8 shows little chance for SegE. Once mean QI<20 or SS<8, the probability of SegE increases as QI SD increases.
When combined with a signal quality parameter, the variation of signal quality between A-scans provides significant information about the quality of an OCT scan and can be used as a predictor of segmentation error.
PMCID: PMC3375178  PMID: 21900227

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